Brain damage monitor

ABSTRACT

An impedance monitor (100) is adapted for use in long-term monitoring of intracellular (neuronal) swelling in the brains (102) of mammals over periods of hours or days. The monitor has an electrically isolated current source (103), supplying a one microampere AC square waveform at 200 Hz. This current is passed through an outer pair of electrodes (104, 105) of a four-electrode arrangement having skin electrodes, extradural electrodes, or in some cases surface electrodes embedded in surgical retractors. Sensing electrode pairs (107, 108) may also detect EEG activity. Impedance changes are displayed graphically (109). Multiple electrode arrays may be used for localization of affected portions of the brain. Even trans-cranially measured impedances reflect intracellular oedema and are clinically useful indicators of treatment efficacy and outcome in cases of ischaemia, asphyxia, trauma, and the like.

FIELD OF THE INVENTION

This invention relates to the monitoring and management of oedema incertain tissues, in particular intracellular oedema within the brains ofmammals, and the assessment of swelling following injury by me ofelectrical impedance measurements. It is adapted for long-termmonitoring using suitable externally applied electrodes and alsoshort-term monitoring of tissue trauma during surgery where surgicaltools having embedded electrodes are used. The invention disclosesmpedance monitoring equipment, and a method for use of the equipment.

BACKGROUND

The monitoring of patients with acute head injuries, whether caused byexternally induced trauma such as birth or accident, or by circulatoryproblems, has hitherto relied upon clinical signs but these may notappear until a time at which the damage may have become at leastpartially irreversible.

Electroencephalography (EEG) tests preferably also including a frequencyanalysis device to reduce the data and indicate electrical activity ismore suitable, though impractical outside a controlled environment.(Reliable EEG measurements require electrical screening from outsideinterference, a motionless subject, and relatively complex equipment).

Cerebral oedema is a particular problem during brain surgery, wheremanipulation, such as retraction of parts of the brain almost inevitablyinvolves some alteration to the circulation of blood and extracellularfluids. At present the practice is to release retractors from time totime on an empirical basis, not knowing whether the chosen time isneedlessly early or too late.

It appears that cerebral oedema is particularly significant when itoccurs intracellularly, within neurones. It appears that there is a kindof "self-destruct" process affecting neurones, occurring over a periodafter some types of CNS injury, the effects of which can be amelioratedby clinical management.

There is a clear need for a better detection procedure for the onset ofcerebral oedema, so that steps to alleviate it may be taken as soon aspossible and even before the appearance of clinical signs, therebyproviding for increased survival and better long-term prospects ofpatients.

OBJECT

It is an object of the present invention to provide an improved systemfor the measurement of oedema of the central nervous system, or onewhich will at least provide the public with a useful choice.

STATEMENT OF THE INVENTION

In one broad aspect the invention provides means capable of repeatedlymeasuring the impedance of the whole brain or parts thereof of livingmammals, thereby indicating the state of normality of the tissues undertest

More particularly the test indicates the amount of extracellular fluidpresent.

Preferably the measurement procedure is non-invasive and does notinterfere with brain function.

In a related aspect the invention provides impedance measuring equipmentsuitable for use in cranial or intracranial impedance measurements ofnervous tissue.

Preferably a four-electrode test arrangement is used.

Preferably a synchronous detector is used to detect an AC voltagedeveloped as a result of an alternating current applied to the tissueunder test.

Preferably the frequency used is a frequency between 3 Hz and 3 KHz.

More preferably the frequency used is between 30 Hz and 150 Hz.

Preferably the current is between ten microamperes and 0.1 microamperes.

More preferably the current is of the order of one microampere.

Preferably the current used is physiologically acceptable and issubstantially below potentially harmful limits, even if usedcontinuously over a period.

Preferably the impedance measurement is averaged over time so thatartefacts resulting from effects such as pulsatile blood flow orinadvertent muscle movements are substantially not apparent.

Preferably the equipment is portable and preferably it is electricallyisolated,

Optionally it may simply indicate the absence or presence of a state ofoedema, though preferably an analogue indication is provided,

More preferably a graphical indication showing the time course of themeasured impedance is provided so that the time course or evolution of apossible state of oedema is made apparent.

In another broad aspect the invention provides contact electrodessuitable for external application to the skin of the head and being heldin place by a compliant band, or by suction or by adhesion.

In a related aspect the invention provides contact electrodes eitherburied within the contact surfaces of a surgical retractor or applied asa flexible membrane directly beneath the retractor when in use, so thatthe electrode surfaces make intimate contact with the tissue undergoingretraction.

Preferably a four-electrode configuration is used wherein one pair ofelectrodes supplies current and the other pair detects a signal.Alternatively more than four electrodes may be used and this may allowfor at least partial localisation of the injured area or areas.

In yet another broad aspect the invention comprises a method forassessment of the outcome of injury resulting in pathological processesaffecting cells within a portion of an animal, including a human,comprising the steps of (a) applying a first pair of electrodes aboutthe periphery of the portion, (b) applying a second pair of electrodesalso about the periphery of the portion, (c) generating an alternatingcurrent at a known current level, (d) applying the alternating currentbetween the second pair of electrodes, (e) detecting and measuring thealternating voltage developed between the first pair of electrodes, (f)repeatedly calculating the impedance of the portion, and (g) noting thetime course of any changes in the impedance.

In a related aspect the invention comprises a method for assessment ofthe outcome of neural injury resulting in pathological processesaffecting cells of the central nervous system of an animal, including ahuman, further comprising the steps of (a) applying the electrodes tothe cranium, (b) repeatedly calculating the impedance of the cranium,and (c) including the time course of any changes in the impedance inevaluation of the effects of the injury, wherein a substantiallyelevated and maintained impedance tends to support a poor prognosis.

In a further related aspect the invention comprises a method wherein theelectrodes are applied directly to the central nervous system.

In a subsidiary aspect the invention uses an alternating current at afrequency of between three Hertz and three thousand Hertz.

Preferably the frequency of the alternating current is between thirtyand three hundred Hertz.

Preferably the waveform of the alternating current is substantially asquare wave.

Preferably the amplitude of the alternating current is substantiallyhold at a value selected from the range of between 0.1 microamperes and10 microamperes,

In a further broad aspect the invention comprises a method of measuringthe impedance of an object (comprising living tissue) in which theduration of substantially continuous measurement exceeds one hour.

In yet another broad aspect the invention comprises apparatus capable ofdetermining the electrical impedance and monitoring changes of theelectrical impedance of an object having intrinsic electrical activity,comprising means capable of generation of an alternating current at aknown current level, means capable of measuring the voltage dropproduced across a first pair of electrode means as a consequence of thepassage of the alternating current between a second pair of electrodemeans and through the object, characterised in that the measurementmeans is capable of coherent detection or demodulation of the voltagedeveloped between the first pair of electrodes.

Preferably the means capable of generation of the alternating current iscapable of providing a synchronisation signal to the means capable ofcoherent detection,

In still another broad aspect the invention provides a method forevaluation of the oedema within nervous tissue by means of themeasurement of impedance.

More particularly the invention provides a method of monitoring thecerebrum in order to detect adverse cerebral events characterised inthat it is a method of monitoring non-pulsatile cerebral tissueimpedance.

Under this aspect the invention relates to methods wherein a patient isundergoing intensive care.

Under this aspect the invention also relates to methods wherein apatient is undergoing cardiac surgery.

Under this aspect the invention further relates to methods wherein apatient is undergoing neurosurgical retraction of the brain.

DRAWINGS

The following is a description of a preferred form of the invention,given by way of example only, with reference to the accompanyingdiagrams.

FIG. 1: is a block diagram of a preferred device for measuring theimpedance between electrodes, showing a preferred method of connection.

FIG. 2: is an illustration of a headband bearing an array of contactelectrodes.

FIG. 3: is an illustration of the contact surface of a surgicalretractor bearing a built-in electrode array.

FIG. 4: is an illustration of a disposable contact electrode; a flexiblemembrane bearing a surface "printed" or metallised electrode array.

FIG. 5: is an illustration derived from an experimental trial, in whichthe duration of ischaemia is compared with the extent of impedancechange over a short and a longer period.

FIG. 6: is an illustration comparing EEG measurements and corticalimpedance (foetal sheep).

FIG. 7: is a circuit diagram of the AC current source portion of animpedance measuring device.

FIG. 8: is a circuit diagram of the balanced detector portion of animpedance measuring device.

FIG. 9: is an illustration of a battery-powered stimulator for use in atelemetered impedance monitoring arrangement.

FIG. 10: is a graph comparing cortical impedance and certain amino acidsas extracted from dialysate (foetal sheep).

FIG. 11: is a further graph from the experiment shown in FIG. 12 (foetalsheep).

FIG. 12: is a graph of temperature, impedance, and EEG intensity (foetalsheep).

FIG. 13: is a graph of cortical impedance, EEG spectral edge frequency,and EEG intensity, of a neonatal grade III encephalopathy, with anunfavourable outcome.

FIG. 14: is a graph of cortical impedance, EEG spectral edge frequency,and EEG intensity, of a neonatal grade I encephalopathy, having afavourable outcome.

PREFERRED EMBODIMENT

Although this invention may be applied to any part of the body in whichoedema of a substantial fraction of the internal tissues are liable todevelop oedema, such as the thorax, most of our experiences are inrelation to cerebral oedema and its measurement.

The underlying principle is believed to be that when extracellular fluid(i.e. oedema) builds up in a tissue--and in particular within nervoustissue wherein the presence of structures (such as myelinated tracts)giving a relatively low conductivity is well-described, the conductivityof the tissue rises as the ion-containing, extracellular fluid providesmore conduction paths. Typical values for white matter are 700 ohm-cmand for grey matter, 300 ohm-cm. The skull is typically 5000 ohm-cm

On the other hand, cytotoxic agents causing cell swelling will tend toreduce the extracellular space and hence the cross-section of relativelyconductive material, and thereby cause the tissue impedance to rise.Here, the cells of particular interest are the neurones themselves, butglial cells are also likely to be important

Should a given pathological process instead cause intracellular wateraccumulation, the tissue conductivity may actually fall and thereforethe impedance will rise. For example certain cytotoxic substances maycause neuronal or glial swelling, and the extracellular space isconsequently reduced. Therefore unthinking acceptance of the validity ofimpedance measurements as an indication of cortical normality may not bewise. On the other hand, cortical impedance measurements, in combinationwith other forms of assessment may assist in the differential diagnosisof a problem case.

In various experimental trials it has been shown that the extent of therise of oedema, as monitored by impedance measurements, has been areliable indication of the outcome of recovery. FIG. 5 illustrated this.In this Fig. the vertical axes all represent activity as a percentage ofthat preceding the ischaemic period. The two left-hand graphs (500, 502)show cranial impedance over a 120-minute period; the right-hand two(501, 503) show the same data (impedance) but over 60 hours. The top twographs (500, 501) relate to a brief ischaemia (shown hatched) which didnot result in long-term damage; the bottom two graphs (502, 503) relateto a longer period (40 minutes--also shown hatched) which did causelong-term damage. Presumably the clinical recording shown in FIGS. 13and 14 similarly reflect different severity of damage.

A comparison of EEG top (intensity) and bottom (median frequency) graphsagainst impedance (central graph) in the same foetal brain experiment isshown in FIG. 6; it appears from this comparison that the impedancemeasurement is a clearer signal.

The principles of the equipment used in our preferred embodiment arethat it is adapted to carry out long-term measurement of the impedanceof cortical tissue using the equipment shown in the summary drawing,FIG. 1. FIG. 1 shows a cranium 101 in section, with a brain 102 within.This example has an electrically isolated current source (103) used toapply a one microampere AC square waveform, at preferably 200 Hz acrossa pair of electrodes (104, 105). Sensing electrodes (107, 108) are takenoptionally through the amplifying section of an EEG machine if one ispresent, and after amplification are connected to a coherent detector(106).

A coherent detector is one that accepts an input carrying informationproviding the phase of the AC signal to be detected, as well asaccepting an input carrying the signal itself; perhaps embedded inother, undesired signals. The detector can be created using a balancedmodulator/demodulator integrated circuit. In this instance, itsoperation can be understood by considering the detector to comprisemeans to sum both positive-going and negative-going portions (convertedto positive-going portions) of the received test signal, while anysignals not coherent with the test signal as presented to the detector'sphase input tend to cancel out and be summed to zero.

The direct (albeit isolated) connection from the source to the coherentdetector carries the phase information. Impedance output changes (at109) are usually filtered from high-frequency components, and may bedisplayed graphically.

This four-terminal approach has the advantage that the frequent andusual effects of resistance in the interface between the any electrodeand the underlying tissues is minimised. Use of a current sourceprovides for a known current traversing the tissue under test, and asthe detected variable is an AC voltage, connection defects such aselectrode potentials are rejected. The array of four electrodes may beplaced either in direct contact with the tissue to be monitored as inthe case of a neurosurgery--in which case a retractor of the type showndiagrammatically in FIG. 3 (incorporating electrodes which will be incontact with brain tissue which is being retracted or otherwise handledand which will deteriorate with time) may be used, or (more usually)indirect measurement through the skin and skull of an intact head may beused, with electrode within a compliant headband as shown in FIG. 2.Preferably the electrodes are of chlorided silver, or carbon, or anyother suitable material used in bio-electrical electrodes. Theelectrodes 21,23, and 22,24 are connected via wires (not shown) to themeasuring instrument. Use of a four-electrode technique renders themeasurement procedure substantially independent of electrode contactresistance effects.

Alternatively more than four electrodes may be placed on a cranium(though usually only four will participate in any one measurement) andthis greater number may allow for at least partial localisation of theinjured area or areas. The electrode array of an EEG instrument maysuffice--with some electrode pairs being "borrowed" for use in supplyingthe AC test current.

Preferably an alternating current is generated and monitored both forreasons of polarisation problems with DC-carrying electrodes and withintissues, and also for reasons of case of detection. Preferably the upperfrequency limit of this current is somewhere between 140 and perhaps upto 3 KHz where capacitative effects become significant; 150 HZ has beenfound a reasonable value although preferably multiples of the powermains frequency used in the locality should be avoided, Also, dominantfrequencies in an EEG are preferably avoided. Examples of these arethose associated with epileptiform seizures. A (substantially) squarewave AC current may be current-regulated for the majority of each cycleby active circuitry, or a sinewave current may be "regulated" or atleast made into an approximation of a current source by the use of ahigh-voltage source with a high-value series resistance.

As capacitative loading of the electrodes is preferably avoided, higherfrequencies are less suitable. A 150 Hz signal is high enough infrequency to not interfere with concurrent EEG recordings. At the lowlimit, frequencies of as little an 3 Hz are effective although 30 Hzupwards are preferred. Our example circuit (FIGS. 7 and 8) generates a200 Hz signal and filters the impedance output signal with a 20 Hzlow-pass filter.

In order to minimise sensing electrode polarisation, the electrodes arecoupled to very high impedance preamplifiers, preferably with drivenguards or shielding about the sense wires, to minimise capacitativeloading.

Preferably the alternating test current is small enough to cause nophysiological effects, and preferably it is further reduced by an amplesafety margin, in case of delayed effects. (Some clinical cases are onthe threshold of an epileptiform seizure). A current of 0.2 microampereshas been used successfully. An approximately 10-100 microvolt signal maybe detected from this current level, and extracted from noise andunwanted electrical signals by techniques such as coherent detection,

Previous attempts to measure cerebral impedance generally used signalsdeveloped by currents of over 100 times the above amplitude--that is,about 100 microamperes--with suitable direct AC voltmeter recordings andit is possible that such currents could trigger or exacerbate neuralactivity, particularly over long periods, or could cause electrodedrifts.

Preferably the alternating current is developed from within an isolated,or electrically floating current generator. The two outputs from thisgenerator are (a) an attenuated substantially square waveform applied toone of each pair of electrodes as shown in FIGS. 1 to 4, (104 and 105,21 and 23, 33 and 36, and 42 and 44) and (b) an optically isolated,synchronising square wave for internal use in coherent signal detection.

Preferably the sensed current, picked up from a sense pair of electrodes(107 and 108, 22 and 24, 34 and 37, or 43 and 45) is amplified within ahigh-impedance difference amplifier capable of rejecting signals commonto both inputs. It is advantageous to use the technique of coherentdetection, in order to reject artefacts due to intrinsic electricalactivity (EEG or ECG, for example) or external interference during theprocess of rectification into direct current. Preferably the common-moderejection performance is enhanced with an isolated amplifier--thoughthis may be most useful in monitoring acute cases in uncontrolledenvironments.

Because blood flow pulsations and the like influence the impedancevalues in measurements that resolve to within one second periods, weprefer to use a low-pass filter so that events of durations less thantypically 10 or even 60 seconds are discarded.

The direct current from the low-pass filter is further amplifiedaccording to the requirements of the display medium, and is indicated tothe user by a preferred means. Preferred display means include graphicaldisplays, most preferably involving a paper record from a pen chartrecorder or a simulation of one with a computer and an optional printer.Such displays allow one to interpret a reading at any particular time inthe light of past trends. Alternatively, the instrument could bemanufactured so as to simply show a present reading in analogue ornumeric terms, or even more simply, to show by means of a visible oraudible (alarm) signal when a preset threshold has been exceeded.Results have been expressed simply in terms of percentage change asreferred to the normal or initial value--although quantitation ispreferred

Optionally a microprocessor or other numerical evaluation means may beincorporated so that the instrument can take account of such factors asthe initial impedance value and/or the rate of change of impedancebefore presenting a measurement or an alarm signal.

The retractor shown diagrammatically as 30 in FIG. 3 may be used duringneurosurgery as a retractor to apply traction to a part of the brain,while the non-toxic embedded electrodes shown as 33 . . . 36 may beconnected to impedance measuring equipment of the type described abovefor concurrent monitoring of oedema. (Connecting wires are not shown).In use a tension applied from the left to the handle 31 causes braintissue adjacent to the tongue 32 and its embedded electrodes 33 . . . 36to be compressed, thereby exposing other areas. Preferably the retractoris a disposable item made of a tough, non-conducting plastic material sothat electric currents are not shunted through its tongue 32. This is anidealised diagram. Other types of neurosurgical retractor may also bemanufactured with similar embedded sets of electrodes. Alternatively aflexible membrane as shown in FIG. 4 might be manufactured upon anon-conducting film 40, carrying a set of surface electrodes 42, 43, 44,and 45, surrounding guard conductor 46 and connecting wires (all ofwhich may be a pattern of deposited metal films laid down as if on aprinted circuit) on one side and connected to a multiconductor wire 41;this may be placed beneath any conventional retractor with theelectrodes in contact with the tissue to be monitored The assembly ofFIG. 4 is preferably sterile, and disposable.

This flexible planar type of sensor array may also be useful forimpedance measurements during (for example) heart surgery when theextent and effects of cardioplegia on the heart require to be monitored.

More details of the actual impedance monitor are given in FIGS. 7 and 8.FIG. 7 is the current source and comprises an isolated power supply, alow-frequency oscillator, a current source to supply a test current, anda buffer to provide a synchronising signal to the detector of FIG. 8. Itcorresponds to block 103 of FIG. 1. The isolated power supply is anAD210 module located at top right of the drawing, This is capable ofgenerating an acceptable (for medical applications) dual-voltage powersupply at +15V and -15V to the remainder of the circuit. (Its unusedisolated analogue channels are reserved for future fault-detectionpurposes). Hollow triangular earth symbols are the isolated earths:parallel-line earth symbols are the non-isolated chassis earth point.Thus connectors C and E supply power to the isolation amplifier, and Aand D are unused. A low-frequency oscillator operating at about 200 Hzis made from a 2N3819 unijunction transistor capacitatively coupled toan AD648 buffer and filtering amplifier. One branch of the output is fedto an AD548 used as an inverting high-gain buffer and then through a6N138 optical isolator shown at bottom center of FIG. 7 to provide asynchronising signal (at connector b) to the detector of FIG. 8 Theother branch of the output is passed through gain and offset controls toa current source comprising a pair of AD648 operational amplifiers; theupper one being a power and feedback regulating stage; sensing abuffered voltage from across the 1M ohm current-to-voltage converter andreturning a signal to the input of the upper amplifier. 510K resistorslimit worst-case failure currents to the brain to a maximum of about 15μA.

FIG. 8 shows the synchronous demodulator and filtering stage used toextract a voltage (placed at "IMPEDANCE OUT") proportional to themeasured impedance which is substantially free of artefactual signalsfrom electrical interference, the electroencephalogram, muscle and heartactivity, and movement artefacts. It corresponds to blocks 106 and 109of FIG. 1.

A conventional electroencephalogram (EEG) amplifier actually detects thesignals resulting from the stimulus signal. Advantages of using aconventional amplifier include that there is usually a requirement tomonitor the EEG as well in clinical applications, and the sameelectrodes can perform both tasks. Alternatively one of the well-knowndifferential preamplifier circuits can be used, with a frequencyresponse limited to below about 300 Hz. The signal from this amplifier,including impedance-related component, arrives at the top right of thiscircuit and is fed through AC-coupled active filters and an X4gain/buffer stage to an AD630 balanced modulator/demodulator integratedcircuit (Analog Devices, USA) controlled by square-wave signals ofselectable polarity coming into this circuit at input B at top left. Acoherent detector such au this device in this circuit operates byrepeatedly either adding or subtracting the incoming signal according tothe phase of its control signal, thereby reinforcing the impedancesignal developed from either polarity of test current, while averagingout any other signals. (In order to minimise interference we prefer tooperate the oscillator of FIG. 7 away from dominant frequencies ofeither the EEG or of likely mains interference. A future device may usea variety of frequencies in order to minimise measurement artifacts

An active filter (device: LTC1062) acts as a 5th order low-pass filterwith a 3 dB point at 20 Hz. The impedance output at lower right isprovided with a gain-settable buffer so that the output can be trimmedto match the input requirements of a chart recorder, analogue-to-digitalconverter, or the like.

Impedance variations typically occur at a slow rate of at most about 10%of full range per minute and the impedance signal can successfully beseparated out from other signals and presented as a substantiallyreliable output.

FIG. 9 shows an alternative current source adapted for long-termapplication with a +,- 1.5V battery-driven supply (909,910). C-MOSSchmitt trigger gates 901, 902 (both 1/4 CD4093) form a relaxationoscillator generating a slow AC square wave coupled through a 1 μFcapacitor 905 to an output buffer amplifier. Frequency-setting partsinclude 907 and 908, 1 M ohms. and capacitor 906, 14.7 πF. The 150Koutput resistor 913 provides (with resistor 904 at 300K, 5 μA at theoutput 914, or with 904 at 3M, 0.5 μA). The operational amplifier is anICL 7611. No provision is shown for a synchronising output for asynchronous detector. Unused Schmitt NAND gates 911, 912 are tied low sothat their current consumption remains low. The circuit current drain is12.5 μA giving a life of about 4 months with type 392 38 μmA/Hbatteries. This stimulator or current source can be used with atelemetry system.

LABORATORY ANALYSIS SOFTWARE.

A package of software has been written for use with an IBM-PC orcompatible computer using "LABVIEW" (National Instruments, USA) tocontrol real-time data acquisition, perform calibration/recalibration,carry out real-time analysis such as power spectral analysis, storeresults, and display information graphically--even historicalinformation--during collection.

Modalities that may be collected over a long period, optionallydisplayed, and recorded in files on a hard disk after collection by theappropriate transducer or electrode array, then after amplification andsignal processing include: EEG spectra, blood pressure, EKG (heartbeat)rate, body temperature, nuchal electromyogram (EMG), and impedance,

For example the last hour of data may be shown during an experiment forsupervisory purposes, and data may be recalled and examined in greaterdetail such as over a short time period, in a clinical application, aversatile status monitoring device such as this may be called on toreview past data without interrupting the continuing collection of astream of data. The recorded data is inherently compatible withtransmission to a remote site for evaluation.

CLINICAL TRIALS

In order to demonstrate and clarify the meaning of impedancemeasurements we have carried out a number of trials using animal models,and a limited number of observations in human infants affected byperinatal asphyxia. The underlying assumption or model is that theimpedance of central nervous tissue represents the volume ofextracellular current-carrying paths predominantly comprising ionisedfluids and if neurones are caused to swell by some abnormal process,this volume is reduced and the impedance rises, as per FIG. 5.

In relation to the "abnormal process" above, FIGS. 10 and 11 togethershow concurrent records from a foetal sheep experiment in which ahypoxic/ischemic insult was applied at 0 hours. This data showsimpedance changes as in other experiments which are here correlated tochemical indicators of toxicity to cells within the central nervoussystem. Concentrations of chemicals were measured with amicrodialysis/HPLC setup which sampled the extracellular fluid withinthe affected part of the brain. Citrulline is a by-product of nitricoxide (NO) synthesis, thus the citrulline curve is believed to becorrelated with nitric oxide synthesis. The "excitotoxic index" is theproduct of (glutamate * glycine)/GABA and was calculated to derive aquantitative descriptor reflecting the composite magnitude of theexcitatory, compared with the inhibitory neurotransmitters presentgenerally through the CNS tissue in the region under test. Thisexcitotoxic index is believed to be related to neuronal swelling orintracellular oedema, and pathological processes within the neurones.The similarity in trends between the excitotoxic index and the impedancesuggests that the continuous measurement of impedance offers anaccessible and simple method by means of which changes in theexcitotoxic index can be inferred.

This experiment, like many others in our series, exhibits what appearsto be a secondary phase of neuronal damage some hours after the initialinsult. Note that the cortical EEG and spectral edge records showepileptiform seizure activity, (shown also by spike activity on the rawEEG) and note that the impedance rises to a peak at around 32 hoursafter occlusion.

FIG. 12 shows, for a sheep experiment, records of the effect oftemperature on impedance. It is useful to quantify the effects oftemperature particularly if mild hypothermia is likely to be used as atype of treatment. A period of reduced temperature was induced for about44 hours. During that time the impedance shows a mall step rise whichtends to mirror the extradural temperature and which substantiallyreturns to the original value on restoration of the former temperature.

FIG. 13 shows records from a case of human neonatal asphyxia; with thehorizontal axis showing time; this recording started at 2.5 hours ofage. The top graph indicates the biparietal EEG intensity and a numberof seizures are evident. The drug paraldehyde was administered as a highdose at the three sites marked by arrows, and the seizures wereeventually quelled The EEG spectral edge (that frequency below which 95%of the EEG power exists at a given moment) also shows the presence ofseizures snd after about 60 hours (3600 minutes) a trend to lowerfrequencies. Meanwhile the cerebral impedance graph shows a rising trendfrom about the time that the seizures commenced. Impedance remained atan abnormally high level from about 45 hours. This case bad anunfavourable outcome and was graded as a Grade III encephalopathy

FIG. 14 (with a shorter time scale) shows records from a second case ofhuman neonatal asphyxia; with the horizontal axis showing time. The topgraph indicates the biparietal EEG intensity and no seizures areevident. The EEG spectral edge (that frequency below which 95% of theEEG power exists at a given moment) shows no seizures and the cerebralimpedance graph shows a substantially constant line. This case had afavourable outcome, and was rated as a grade I encephalopathy.

Presumably a clinician would use a continuous EEG recording as adeterminant of the need for medication to prevent seizures, while theimpedance measurement appears to indicate damage so far; which may atleast qualitatively if not quantitatively indicate the need for certainfurther treatments, and appears to be particularly useful in indicatingthe final outcome of the case,

It is tempting to surmise that events occurring at the time of theseizures at about 20 hours caused neural insults resulting inintracellular oedema and possibly the seizures themselves release toxicmaterials; leading to the possibility that treatments having the effectof modulating neuronal activity and in particular seizures (which areoften not clinically apparent as movement disorders) may be quitebeneficial in management of these cases. We can say that the impedancerises when a number of seizures are occurring, and that without an EEG aclinical would probably not be aware that a seizure was occurring a all.Instrumentation is clearly useful. Further studies using cerebralimpedance as a measure of "neuronal health" are continuing.

Finally, it will be appreciated that various alterations andmodifications may be made to the foregoing without departing from thescope of this invention as described in this specification.

I claim:
 1. A method for assessment of the outcome of brain injuryresulting in pathological processes affecting cells within a portion ofin animal, including a human, comprising the steps of(a) applying afirst pair of electrodes about the periphery of the portion, (b)applying a second pair of electrodes also about the periphery of theportion, (c) generating an alternating current at a known current level,(d) applying the alternating current between the second pair ofelectrodes, (e) detecting and measuring the alternating voltagedeveloped between the first pair of electrodes, (f) repeatedlycalculating the impedance of the portion, and (g) noting the time courseof any changes in the impedance.
 2. A method as claimed in claim 1 forassessment of the outcome of neural injury resulting in pathologicalprocesses affecting cells of the central nervous system of an animal,including a human, further composing the steps of(a) applying theelectrodes to the cranium, (b) repeatedly calculating the impedance ofthe cranium, and (c) including the time course of any changes in theimpedance in evaluation of the effects of the injury, wherein asubstantially elevated and maintained impedance tends to support a poorprognosis.
 3. A method as claimed in claim 2 wherein the electrodes areapplied directly to the central nervous system.
 4. A method as claimedin claim 3 wherein the current is an alternating current at a frequencyof between three Hertz and three thousand Hertz.
 5. A method as claimedin claim 4 wherein the frequency of the alternating current is betweenthirty and three hundred Hertz.
 6. A method as claimed in claim 5 inwhich the waveform of the alternating current is substantially a squarewave.
 7. A method as claimed in claim 6 wherein the amplitude of thealternating current is held substantially at a value selected from therange of between 0.1 microamperes and 10 microamperes.
 8. A method asclaimed in claim 7 in which the duration of substantially continuousmeasurement exceeds one hour.
 9. Apparatus capable of determining theelectrical impedance and monitoring changes of the electrical impedanceof a damaged brain, comprising means capable of generation of analternating current at a known current level, means capable of measuringthe voltage drop produced across a first pair of electrode means as aconsequence of the passage of the alternating current between a secondpair of electrode means and through the brain, characterised in that themeasurement moans is capable of coherent detection or demodulation ofthe voltage developed between the first pair of electrodes. 10.Apparatus as claimed in claim 9, wherein the means capable of generationof the alternating current is capable of providing a synchronisationsignal to the means capable of coherent detection.